The present invention relates to novel lipid A analogs having excellent macrophage activity inhibitory action and useful as an anti-inflammatory agent or a medicament against autoimmune diseases or septicemia.
The outermost layer of the cell wall of gram negative bacteria obtained from enterobacteria contains a toxic component (endotoxin) which is not secreted out of the cell. This endotoxin exhibits, in addition to its endotoxic activity, various biological activities such as immunoadjuvant activating action which is related to biophylaxis, macrophage activating action, mitogen activating action, fever producing action, tumor necrosis action, antibody production enhancing action and TNF inducing action.
It has been confirmed that this endotoxin is composed of a lipopolysaccharide and a portion called xe2x80x9clipid Axe2x80x9d which is an active center of endotoxic activity (Imoto et al., Tetrahedron Letters, 26, 1545 (1985)).
It has also been revealed that lipid X and lipid Y, each of which is a monosaccharide separated from a variant of E. coli as a precursor for biosynthesis of lipid A, exhibit similar activities to lipid A.
Based on these results, attempts to synthesize derivatives of lipid A, X or Y having useful activity, among the above-described various activities, have been made frequently For example, known is a derivative as described in Japanese Patent Application Laid-Open No. Hei 10-324694.
An object of the present invention is to find a novel lipid A derivative having excellent macrophage activity inhibitory action and useful as an anti-inflammatory agent or a medicament against autoimmune diseases or septicemia.
The present inventors have made a great effort toward fulfilling the above-described object. As a result, it has been found that some series of ether type lipid A 1-carboxylic acid analogs exhibit excellent macrophage activity inhibitory action, leading to the completion of the present invention.
The compounds of the present invention have the general formula (I): 
wherein:
R1 and R3 may be the same or different and each represents a C1-C20 alkanoyl group which may optionally be substituted with one or more substituent groups selected from substituent group A, a C3-C20 alkenoyl group which may optionally be substituted with one or more substituent groups selected from substituent group A or a C3-C20 alkynoyl group which may optionally be substituted with one or more substituent groups selected from substituent group A;
R2 and R4 may be the same or different and each represents a C1-C20 alkyl group which may optionally be substituted with one or more substituent groups selected from substituent group A, a C2-C20 alkenyl group which may optionally be substituted with one or more substituent groups selected from substituent group A or a C2-C20 alkynyl group which may optionally be substituted with one or more substituent groups selected from substituent group A;
R5 is a hydrogen atom, a halogen atom, a hydroxy group, a C1-C6 alkoxy group which may optionally be substituted with an oxo group, a C2-C6 alkenyloxy group which may optionally be substituted with an oxo group, or a C2-C6 alkynyloxy group which may optionally be substituted with an oxo group;
Substituent group A is a group consisting of a halogen atom, a hydroxy group, an oxo group, a C1-C20 alkoxy group which may optionally be substituted with an oxo group, a C2-C20 alkenyloxy group which may optionally be substituted with an oxo group, a C2-C20 alkynyloxy group which may optionally be substituted with an oxo group, a C1-C20 alkanoyloxy group which may optionally be substituted with an oxo group, a C3-C20 alkenoyloxy group which may optionally be substituted with an oxo group, or a C3-C20 alkynoyloxy group which may optionally be substituted with an oxo group;
or a pharmaceutically acceptable salt or ester thereof.
Preferred compounds of the present invention are:
2) a compound wherein R1 is a C4-C18 alkanoyl group optionally substituted with one or more substituent groups selected from substituent group A;
3) a compound wherein R1 is a C8-C16 alkanoyl group optionally substituted with one or more substituent groups selected from substituent group A;
4) a compound wherein R1 is an unsubstituted C12-C14 alkanoyl group or a C12-C14 alkanoyl group substituted with a hydroxy group;
5) a compound wherein R1 is an unsubstituted lauroyl or myristoyl group or a lauroyl or myristoyl group substituted with a hydroxy group;
6) a compound wherein R2 is a C4-C18 alkyl group optionally substituted with one or more substituent groups selected from substituent group A;
7) a compound wherein R2 is a C8-C16 alkyl group optionally substituted with one or more substituent groups selected from substituent group A;
8) a compound wherein R2 is an unsubstituted C12-C14 alkyl group or a C12-C14 alkyl group substituted with a hydroxy group;
9) a compound wherein R2 is an unsubstituted dodecyl or tetradecyl group or a dodecyl or tetradecyl group substituted with a hydroxy group;
10) a compound wherein R3 is an unsubstituted C1-C16 alkanoyl group;
11) a compound wherein R3 is an unsubstituted C1-C8 alkanoyl group;
12) a compound wherein R3 is an unsubstituted C1-C4 alkanoyl group;
13) a compound wherein R3 is an acetyl group or a propionyl group;
14) a compound wherein R3 is an acetyl group;
15) a compound wherein R4 is a C4-C18 alkyl group optionally substituted with one or more substituent groups selected from substituent group A;
16) a compound wherein R4 is a C8-C16 alkyl group optionally substituted with one or more substituent groups selected from substituent group A;
17) a compound wherein R4 is a C12-C14 alkyl group substituted with a fluorine atom, a hydroxy group, an unsubstituted C12-C14 alkoxy group or an unsubstituted C12-C14 alkanoyloxy group;
18) a compound wherein R4 is a dodecyl group or a tetradecyl group substituted with a dodecyloxy group or a tetradecyloxy group;
19) a compound wherein R4 is a dodecyl group or a tetradecyl group substituted with a lauroyloxy group or a myristoyloxy group;
20) a compound wherein R5 is a halogen atom, a hydroxy group or an unsubstituted C1-C6 alkoxy group; or
21) a compound wherein R5 is a fluorine atom, a hydroxy group or a methoxy group.
More preferred compounds are selected from:
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-6-O-methyl-4-O-phosphono-3-O-{(R)-3-tetradecanoyloxytetradecyl}-xcex2-D-glucopyranosyl]-3- {(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-4-O-phosphono-3-O-{(R)-3-tetradecanoyloxytetradecyl}-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
2,6-anhydro-7-O-[2-acetylamino-2,6-dideoxy-6-fluoro-4-O-phosphono-3-O-{(R)-3-tetradecanoyloxytetradecyl}-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-3-O-{(R)-3-dodecyloxytetradecyl}-6-O-methyl-4-O-phosphono-xcex2-D-glucopyranosyl]-3-{(R)-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-3-O-{(R)-3-dodecyloxytetradecyl}-4-phosphono-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid; or
2,6-anhydro-7-O-[2-acetylamino-2,6-dideoxy-3-O-{(R)-3-dodecyloxytetradecyl}-6-fluoro-4-O-phosphono-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid.
The present invention includes a medicament containing a compound of formula (I) as an active ingredient, especially a composition for the treatment or prophylaxis of an inflammatory disorder, a composition for the treatment or prophylaxis of an autoimmune disease or a composition for the treatment or prophylaxis of septicemia.
The xe2x80x9cC1-C20 alkanoylxe2x80x9d moiety, which is described in the definition of R1 and R3 as xe2x80x9ca C1-C20 alkanoyl group which may be optionally substituted with one or more substituent groups selected from substituent group Axe2x80x9d and in the definition of substituent group A as xe2x80x9ca C1-C20 alkanoyloxy group which may be optionally substituted with an oxo groupxe2x80x9d, includes a straight or branched chain C1-C20 alkanoyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, isohexanoyl, heptanoyl, isoheptanoyl, octanoyl, isooctanoyl, nonanoyl, isononanoyl, decanoyl, isodecanoyl, undecanoyl, isoundecanoyl, lauroyl, isolauroyl, tridecanoyl, isotridecanoyl, myristoyl, pentadecanoyl, palmitoyl, heptadecanoyl, stearoyl, isostearoyl, nonadecanoyl, or icosanoyl.
A preferred alkanoyl moiety of R1 and substituent group A is a C4-C18 alkanoyl group; a more preferred moiety is a C8-C16 alkanoyl group; a still more preferred moiety is a C12-C14 alkanoyl group; and the most preferred moiety is the lauroyl group or the myristoyl group.
A preferred alkanoyl moiety of R3 is a C1-C16 alkanoyl group; a more preferred moiety is a C1-C8 alkanoyl group; a more preferred moiety is a C1-C4 alkanoyl group; a still more preferred moiety is the acetyl group or the propionyl group; and the most preferred moiety is the acetyl group.
The xe2x80x9cC3-C20 alkenoylxe2x80x9d moiety, which is described in the definition of R1 and R3 as xe2x80x9ca C3-C20 alkenoyl group which may be optionally substituted with one or more substituent groups selected from substituent group Axe2x80x9d and in the definition of substituent group A as xe2x80x9ca C3-C20 alkenoyloxy group which may be optionally substituted with an oxo groupxe2x80x9d, includes a group having 1 to 3 double bonds in the corresponding C3-C20 alkanoyl group described above as the C1-C20 alkanoyl group.
A preferred alkenoyl moiety of R1 and substituent group A is a C4-C18 alkenoyl group; a more preferred group is a C12-C14 alkenoyl group; and the most preferred group is the 9-tetradecenoyl group.
A preferred alkenoyl moiety of R3 is a C3-C16 alkenoyl group; a more preferred moiety is a C3-C4 alkenoyl group; and the most preferred moiety is the 3-butenoyl group. The xe2x80x9cC3-C20 alkynoylxe2x80x9d moiety, which is described in the definition of R1 and R3 as xe2x80x9ca C3-C20 alkynoyl group which may be optionally substituted with one or more substituent groups selected from substituent group Axe2x80x9d and in the definition of substituent group A as xe2x80x9ca C3-C20 alkynoyloxy group which may be optionally substituted with an oxo groupxe2x80x9d, includes a group having 1 to 3 triple bonds in the corresponding C3-C20 alkanoyl group described above as the C1-C20 alkanoyl group.
A preferred alkynoyl moiety of R1 and substituent group A is a C4-C18 alkynoyl group; a more preferred moiety is a C12-C14 alkynoyl group; and the most preferred moiety is the 9-tetradecynoyl group.
A preferred alkynoyl moiety of R3 is a C3-C16 alkynoyl group; a more preferred moiety is a C3-C4 alkynoyl group; and the most preferred moiety is the 3-butynoyl group.
The xe2x80x9cC1-C20 alkylxe2x80x9d group, which is described in the definition of R2 and R4 as xe2x80x9ca C1-C20 alkyl group which may be optionally substituted with one or more substituent groups selected from substituent group Axe2x80x9d includes a straight or branched chain C1-C20 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1 -ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, 4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, icosyl, or 3,7,11,15-tetramethylhexadecyl.
A preferred alkyl group is a C4-C18 alkyl group, a more preferred group is a C8-C16 alkyl group, a still more preferred group is a C12-C14 alkyl group, and the most preferred groups are the dodecyl group or the tetradecyl group.
The xe2x80x9cC2-C20 alkenylxe2x80x9d group, which is described in the definition of fe and R4 as xe2x80x9ca C2-C20 alkenyl group which may be optionally substituted with one or more substituent groups selected from substituent group Axe2x80x9d includes a group having 1 to 3 double bonds in the corresponding C2-C20 alkyl group described above as the C1-C20 alkyl group. A preferred alkenyl group is a C4-C18 alkenyl group, a more preferred group is a C12-C14 alkenyl group, and the most preferred group is the 9-tetradecenyl group.
The xe2x80x9cC2-C20 alkynylxe2x80x9d group which is described in the definition of R2 and R4 as xe2x80x9ca C2-C20 alkynyl group which may be optionally substituted with one or more substituent groups selected from substituent group Axe2x80x9d includes a group having 1 to 3 triple bonds in the corresponding C2-C20 alkyl group described above as the C1-C20 alkyl group. A preferred alkynyl group is a C4-C18 alkynyl group, a more preferred group is a C12-C14 alkynyl group, and the most preferred group is the 9-tetradecynyl group.
The halogen atom in the definition of R5 and substituent group A includes, for example, the fluorine, chlorine, bromine or iodine atom. A preferred halogen atom is the fluorine, chlorine or bromine atom, and the more preferred atom is fluorine. The xe2x80x9cC1-C6 alkoxyxe2x80x9d group, which is described in the definition of R5 as xe2x80x9ca C1-C6 alkoxy group which may optionally be substituted with an oxo groupxe2x80x9d includes, for example, a straight or branched chain C1-C6 alkoxy group such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutyloxy, neopentyloxy, 1-ethylpropyloxy, hexyloxy, isohexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutyloxy, 2,2-dimethylbutyloxy, 1,1-dimethylbutyloxy, 1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,3-dimethylbutyloxy or 2-ethylbutyloxy. A preferred alkoxy group is a C1-C4 straight or branched chain alkoxy group, and the more preferred group is the methoxy group.
The xe2x80x9cC2-C6 alkenyloxyxe2x80x9d group, which is described in the definition of R5 as xe2x80x9ca C1-C6 alkenyloxy group which may optionally be substituted with an oxo groupxe2x80x9d includes a group having 1 to 3 double bonds in the corresponding C2-C6 alkoxy group described above as the C1-C6 alkoxy group. A preferred alkenyloxy group is a C2-C4 alkenyloxy group and the most preferred group is the 3-butenyloxy group.
The xe2x80x9cC2-C6 alkynyloxyxe2x80x9d group, which is described in the definition of R5 as xe2x80x9ca C2-C6 alkynyloxy group which may optionally be substituted with an oxo groupxe2x80x9d includes a group having 1 to 3 triple bonds in the corresponding C2-C6 alkoxy group described above as the C1-C6 alkoxy group. A preferred alkynyloxy group is a C2-C4 alkynyloxy group and the most preferred group is the 3-butynyloxy group.
The xe2x80x9cC1-C20 alkoxyxe2x80x9d group, which is described in the definition of substituent group A as xe2x80x9ca C1-C20 alkoxy group which may optionally be substituted with an oxo groupxe2x80x9d includes, for example, a straight or branched chain C1-C20 alkoxy group, in which an oxygen atom is attached to the C1-C20 alkyl group described above, such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutyloxy, neopentyloxy, 1-ethylpropyloxy, hexyloxy, isohexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutyloxy, 2,2-dimethylbutyloxy, 1,1-dimethylbutyloxy, 1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,3-dimethylbutyloxy, 2-ethylbutyloxy, heptyloxy, 4-methylhexyloxy, 1-propylbutyloxy, 4,4-dimethylpentyloxy, octyloxy, 6-methylheptyloxy, 5,5-dimethylhexyloxy, nonyloxy, decyloxy, 1-methylnonyloxy, 3-methylnonyloxy, 8-methylnonyloxy, 3-ethyloctyloxy, 3,7-dimethyloctyloxy, 7,7-dimethyloctyloxy, undecyloxy, 4,8-dimethylnonyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, 3,7,11-trimethyldodecyloxy, hexadecyloxy, 4,8,12-trimethyltridecyloxy, 1-methylpentadecyloxy, 14-methylpentadecyloxy, 13,13-dimethyltetradecyloxy, heptadecyloxy, octadecyloxy, 1-methylheptadecyloxy, nonadecyloxy, icosyloxy or 3,7,11,15-tetramethylhexadecyloxy group. A preferred alkoxy group is a C4-C18 alkoxy group, a more preferred group is a C8-C16 alkoxy group, a still more preferred group is a C12-C14 alkoxy group and the most preferred group is the dodecyloxy group or the tetradecyloxy group.
The xe2x80x9cC2-C20 alkenyloxyxe2x80x9d group, which is described in the definition of substituent group A as xe2x80x9ca C2-C20 alkenyloxy group which may optionally be substituted with an oxo groupxe2x80x9d includes a group having 1 to 3 double bonds in the corresponding C2-C20 alkoxy group described above as the C1-C20 alkoxy group. A preferred alkenyloxy group is a C4-C18 alkenyloxy group, a more preferred group is a C12-C14 alkenyloxy group and the most preferred group is the 9-tetradecenyloxy group.
The xe2x80x9cC2-C20 alkynyloxyxe2x80x9d group, which is described in the definition of substituent group A as xe2x80x9ca C2-C20 alkynyloxy group which may optionally be substituted with an oxo groupxe2x80x9d includes a group having 1 to 3 triple bonds in the corresponding C2-C20 alkoxy group described above as the C1-C20 alkoxy group. A preferred alkynyloxy group is a C4-C18 alkynyloxy group, a more preferred group is a C12-C14 alkynyloxy group and the most preferred group is the 9-tetradecynyloxy group.
The preferred substitution position of substituent group A in the formula (I) is the 3-position.
Preferably R1 is a C4-C18 alkanoyl group which may optionally be substituted with one or more substituent groups selected from substituent group A. More preferably R1 is a C8-C16 alkanoyl group which may optionally be substituted with one or more substituent groups selected from substituent group A. Still more preferably R1 is a C12-C14 alkanoyl group which may optionally be substituted with one or more substituent groups selected from substituent group A. Most preferably R1 is an unsubstituted lauroyl group or myristoyl group or a lauroyl or myristoyl group substituted with a hydroxy group.
Preferably R2 is a C4-C18 alkyl group which may optionally be substituted with one or more substituent groups selected from substituent group A. More preferably R2 is a C8-C16 alkyl group which may optionally be substituted with one or more substituent groups selected from substituent group A. Still more preferably R2 is a C12-C14 alkyl group which may optionally be substituted with one or more hydroxy groups. Most preferably R2 is an unsubstituted dodecyl group or tetradecyl group or a dodecyl or tetradecyl group substituted with a hydroxy group.
Preferably R3 is an unsubstituted C1-C16 alkanoyl group. More preferably R3 is an unsubstituted C1-C8 alkanoyl group. More preferably R3 is a C1-C14 alkanoyl group. Still more preferably R3 is an acetyl group or propionyl group. Most preferably R3 is an acetyl group.
Preferably R4 is a C4-C18 alkyl group which may optionally be substituted with one or more substituent groups selected from substituent group A. More preferably R4 is a C8-C16 alkyl group which may optionally be substituted with one or more substituent groups selected from substituent group A. Still more preferably R4 is a C12-C14 alkyl group which is substituted with a fluorine atom, a hydroxy group, an unsubstituted C12-C14 alkoxy group, or an unsubstituted C12-C14 alkanoyloxy group. Most preferably R4 is a dodecyl group or tetradecyl group substituted with a dodecyloxy group, a tetradecyloxy group, a lauroyloxy group or a myristoyloxy group.
Preferably R5 is a halogen atom, hydroxy group or an unsubstituted C1-C6 alkoxy group. More preferably R5 is a fluorine atom, a hydroxy group, or a methoxy group.
The compound of formula (I) can be converted to a salt. A preferred salt is an alkali metal salt or an alkaline earth metal salt such as a sodium salt, a potassium salt, a magnesium salt or a calcium salt, or a salt of an organic base such as a triethylamnine salt or a trimethylamine salt.
In some case, when a compound of formula (I) of the present invention is allowed to stand in contact with the atmosphere it may absorb water or may take up water to form a hydrate. The present invention encompasses such hydrates.
In addition, a compound of formula (I) of the present invention may take up a solvent to form a solvate. The present invention encompasses such solvates.
The compound of formula (I) can form an ester and the ester-forming group includes the following groups (a) to (f). These ester groups include protecting groups which can be cleaved by a biological method such as hydrolysis in vivo and protecting groups for a chemical reaction which may be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis.
(a) xe2x80x94CHRaRb 
(b) xe2x80x94CHRcRd 
(c) xe2x80x94(CHRe)nxe2x80x94OCORf 
(d) xe2x80x94(CHRe)nxe2x80x94ORg 
(e) xe2x80x94SiRgRhRi 
(f) xe2x80x94CH2xe2x80x94Phxe2x80x94COORi 
wherein:
n is 1 or 2;
Ph is a phenyl group;
Ra is a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with an aryl group, a halogeno lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aliphatic acyl group, or an aliphatic acyl group substituted with an aryl group. Preferably Ra is a hydrogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, or a lower alkynyl group. More preferably Ra is a hydrogen atom, a C1-C3 alkyl group, a halogeno C1-C3 alkyl group, a C2-C3 alkenyl group, or a C2-C3 alkynyl group.
Rb is hydrogen or a lower alkyl group. Preferably Rb is a hydrogen atom.
Rc is an aryl group or a substituted aryl group (said substituents are a lower alkyl group, a lower alkoxy group, a halogen atom or a nitro group). Preferably Rc is a lower-alkoxylated aryl group, a halogenated aryl group, or a nitrated aryl group. More preferably Rc is a lower-alkoxylated phenyl group, a halogenated phenyl group, or a nitrated phenyl group.
Rd is a hydrogen atom or a group as defined in Rc.
Rc is hydrogen or a lower alkyl group. Preferably Re is a hydrogen atom or a C1-C3 alkyl group.
Rf is a lower alkyl group, a lower alkoxy group or a group as defined in Rc. Preferably Rf is a lower alkyl group or a lower alkoxy group. More preferably Rf is a C1-C3 alkyl group or a C1-C3 alkoxy group.
Re and Rf taken together may be a phthalidyl or a mono- or di-substituted phthalidyl group (said substituent is a lower alkyl group or lower alkoxy group).
Rg and Rh may be the same or different and each represent a lower alkyl group or a group as defined in Rc. Preferably Rg and Rh each represent a lower alkyl group. More preferably Rg and Rh each represent a C1-C3 alkyl group.
Ri is a lower alkyl group and preferably Ri is a C1-C3 alkyl group.
A typical protecting group which may be cleaved by a biological method such as hydrolysis in vivo and a protecting group for a chemical reaction are as follows:
A preferable protecting group which may be cleaved by a biological method is methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, tert-butoxymethyl, phenoxymethyl, acetoxymethyl, pivaloyloxymethyl, cyclopentanoyloxymethyl, 1-cyclohexanoyloxybutyl, benzoyloxymethyl, methoxycarbonyloxymethyl or 2-propoxycarbonyloxyethyl.
A preferred protecting group for a chemical reaction is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 3-methyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-pentenyl, 1-methyl-3-pentenyl, 2-hexenyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, acetylmethyl, benzyl, phenethyl, 3-phenylpropyl, a-naphthylmethyl, xcex2-naphthylmethyl, diphenylmethyl, triphenylmethyl, 6-phenylhexyl, xcex1-naphthyldiphenylnethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl)methyl, 4-methoxycarbonylbenzyl, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiisopropylsilyl, methyl-di-tert-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, or phenyldiisopropylsilyl group.
The compound of formula (I) has some asymmetric centers and can exist as stereoisomers having S- or R-configuration at each asymmetric center. The present invention encompasses an individual isomer or a mixture of these isomers.
The compounds in the following table are intended to illustrate typical compounds of the present invention and are not intended to limit the scope of the invention. In the table the following abbreviations are used:
Ac: acetyl group, Bu: butyl group, Byr: butyryl group, Dc: decyl group, Dco: decanoyl, Ddc: dodecyl group, Ei: eicosyl group, Eicn: eicosanoyl group, Fo: formyl group, Hx: hexylgroup, Hdc: hexadecyl group, Hxn: hexanoyl group, Lau: lauroyl group (dodecanoyl group), Me: methyl group, Myr: myristoyl group (tetradecanoyl group), Oc: octyl group, Odc: octadecyl group, Octo: octanoyl group, xe2x95x90O: oxo group (carbonyl group taken together with carbon), Pal: palmitoyl group (hexadecanoyl group) Prn: propionyl group, Ste: stearoyl group (octadecanoyl group), Tedc: tetradecyl group, Val: valeryl group.
The numbers of preferred compounds in the above table are 1, 2, 3, 7, 8, 9, 12, 13, 14, 45, 46, 47, 51, 52, 53, 56, 57, 58, 89, 90, 91, 96, 97, 98, 102, 103, 104, 108, 109, 110, 114, 115, 116, 120, 121, 122, 126, 127, 128, 132, 133, 134, 138, 139, 140, 144, 145, 146, 150, 182, 183, 184, 194, 234, 240, 252, 263, 264, 265, 276, 282, 287, 316, 322, 327, 380, 386, 391 and 431.
The numbers of more preferred compounds in the above table are 2, 3, 8, 9, 13, 14, 46, 47, 52, 53, 57, 58, 103, 104, 109, 110, 115, 121, 127, 128, 133, 134, 139, 145, 150, 183, 194, 264, 276, 287, 316, 327, 380, 391 and 431.
The most preferred compounds in the above table are:
2 (exemplification compound number in the table):
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-6-O-methyl-4-O-phosphono-3-O-{(R)-3-tetradecanoyloxytetradecyl}-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxydodecanoylamino}-4-O-{(R)-3-hydroxydodecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
8 (exemplification compound number in the table):
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-6-O-methyl-4-O-phosphono-3-O-{(R)-3-tetradecanoyloxytetradecyl}-xcex2-D-glucopyranosyl]-3-tetradecanoylamino-4-O-tetradecyl-3-deoxy-D-glycero-D-ido-heptonic acid;
13 (exemplification compound number in the table):
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-6-O-methyl-4-O-phosphono-3-O-{(R)-3-tetradecanoyloxytetradecyl}-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
46 (exemplification compound number in the table):
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-4-O-phosphono-3-O-{(R)-3-tetradecanoyloxytetradecyl }-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxydodecanoylamino}-4-O-{(R)-3-hydroxydodecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
52 (exemplification compound number in the table):
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-4-O-phosphono-3-O-{(R)-3-tetradecanoyloxytetradecyl}-xcex2-D-glucopyranosyl]-3-tetradecanoylamino-4-O-tetradecyl-3-deoxy-D-glycero-D-ido-heptonic acid;
57 (exemplification compound number in the table):
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-4-O-phosphono-3-O-{(R)-3-tetradecanoyloxytetradecyl}-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
121 (exemplification compound number in the table):
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-4-O-phosphono-3-O-{(R)-3-hydroxytetradecyl}-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
127 (exemplification compound number in the table):
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-4-O-phosphono-3-O-{(R)-3-dodecanoyloxytetradecyl}-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
139 (exemplification compound number in the table):
2,6-anhydro-7-O-[2-acetylamino-2,6-dideoxy-4-O-phosphono-6-fluoro-3-O-{(R)-3-tetradecanoyloxytetradecyl}-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxydodecanoylaamino}-4-O-{(R)-3-hydroxydodecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
150 (exemplification compound number in the table):
2,6-anhydro-7-O-[2-acetylamino-2,6-dideoxy-6-fluoro-4-O-phosphono-3-O-{(R)-3-tetradecanoyloxytetradecyl}-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
287 (exemplification compound number in the table):
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-3-O-{(R)-3-dodecyloxytetradecyl}-6-O-methyl-4-O-phosphono-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylarnino}-4-O-{(R)-3-hydroxyteradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid;
327 (exemplification compound number in the table):
2,6-anhydro-7-O-[2-acetylamino-2-deoxy-3-O-{(R)-3-dodecyloxytetradecyl}-4-O-phosphono-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxytertradecanoylamino}-4-O-{(R)-3-hydroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid; and
391 (exemplification compound number in the table):
2,6-anhydro-7-O-[2-acetylamino-2,6-dideoxy-3-O-{(R)-3-dodecyloxytetradecyl}-6-fluoro-4-O-phosphono-xcex2-D-glucopyranosyl]-3-{(R)-3-hydroxytetradecanoylamino}-4-O-{(R)-3-hdroxytetradecyl}-3-deoxy-D-glycero-D-ido-heptonic acid.
The compound (I) of the present invention can be produced by methods illustrated below using known compounds (II) and (XI) (Carbohydrate Research 222, 57 (1991) as starting materials. 
In the above reaction scheme:
R1, R2, R3, R4 and R5 are as defined above.
R6 and R7 may be the same or different, and each represents hydrogen, a C1-C6 alkyl group, or a C6-C10 aryl group.
R8 is a C1-C20 alkyl group, a C2-C20 alkenyl group, or a C2-C20 alkynyl group which may optionally be substituted with one or more substituents selected from substituent group B.
The substituent group B includes a halogen atom, a protected hydroxy group (said protecting group is preferably a trichloroethoxycarbonyl group or a benzyl group), an oxo group, a C1-C20 alkoxy group which may optionally be substituted with an oxo group, a C2-C20 alkenyloxy group which may optionally be substituted with an oxo group, and a C2-C20 alkynyloxy group which may optionally be substituted with an oxo group.
R9 is a C1-C20 alkanoyl group, a C2-C20 alkenoyl group or a C2-C20 alkynoyl group which may optionally be substituted with one or more substituents selected from substituent group C.
The substituent group C includes a halogen atom, a protected hydroxy group (said protecting group is preferably a trichloroethoxycarbonyl group or a benzyl group), an oxo group, a C1-C20 alkoxy group which may optionally be substituted with an oxo group, a C2-C20 alkenyloxy group which may optionally be substituted with an oxo group, and a C2-C20 alkynyloxy group which may optionally be substituted with an oxo group.
R10 is a C1-C20 alkyl group, a C2-C20 alkenyl group, or a C2-C20 alkynyl group which may optionally be substituted with one or more substituents selected from substituent group D.
The substituent group D includes a halogen atom, a protected hydroxy group (said protecting group is preferably a trichloroethoxycarbonyl group or a p-methoxybenzyl group), an oxo group, a C1-C20 alkoxy group which may optionally be substituted with an oxo group, a C2-C20 alkenyloxy group which may optionally be substituted with an oxo group, and a C2-C20 alkynyloxy group which may optionally be substituted with an oxo group.
R11 is an optionally substituted C6-C10 aryl group, an optionally substituted C7-C11 aralkyl group or a methyl group which may optionally be substituted with 1 to 3 aryl groups. Preferably R11 is a phenyl group, a benzyl group or a diphenylmethyl group.
R12 is a C1-C20 alkyl group, a C2-C20 alkenyl group, or a C2-C20 alkynyl group which may optionally be substituted with one or more substituents selected from substituent group E.
The substituent group E includes a halogen atom, a hydroxy group, an oxo group, a C1-C20 alkoxy group which may optionally be substituted with an oxo group, a C2-C20 alkenyloxy group which may optionally be substituted with an oxo group, and a C2-C20 alkynyloxy group which may optionally be substituted with an oxo group.
R13 is a C1-C20 alkyl group, a C2-C20 alkenyl group or a C2-C20 alkynyl group which may optionally be substituted with one or more substituents selected from substituent group F.
The substituent group F includes a halogen atom, a protected hydroxy group (said protecting group is preferably a trichloroethoxycarbonyl group or a p-methoxybenzyl group), an oxo group, a C1-C20 alkoxy group which may optionally be substituted with an oxo group, a C2-C20 alkenyloxy group which may optionally be substituted with an oxo group, a C2-C20 alkynyloxy group which may optionally be substituted with an oxo group, a C1-C20 alkanoyloxy group which may optionally be substituted with an oxo group, a C3-C20 alkenoyloxy group which may optionally be substituted with an oxo group, a C3-C20 alkynoyloxy group which may optionally be substituted with an oxo group.
R14 is a C1-C4 alkyl group.
R15 is a C1-C6 alkyl group.
R16 is a hydrogen atom or a halogen atom.
R17 is a hydrogen atom, a halogen atom, a protected hydroxy group (said protecting group is a benzyloxycarbonyl group or a diphenylmethyl group), a C1-C6 alkoxy group which may optionally be substituted with an oxo group, a C2-C6 alkenyloxy group which may optionally be substituted with an oxo group, or a C2-C6 alkynyloxy group which may optionally be substituted with an oxo group.
The compound (I) of the present invention is produced through reactions of the following three processes:
(1) Process A is the step for preparation of intermediate (X).
(2) Process B is the step for preparation of intermediate (XXI), (XXIX) and (XXXII). Process B comprises three methods (Method Ba, Method Bb and Method Bc), one of which is selected depending on desired compound (I).
(3) Process C is the step for preparation of compound (D) through a condensation reaction of intermediate (X) obtained in Process A with intermediate (XXI), (XXIX) or (XXXII) obtained in Process B.
Each process is described below.
(Step A1)
This step is a process for preparation of the 2-azido compound (III). This process is accomplished by treatment of a known compound (II) with an azidating reagent in the presence of a base in an inert solvent.
There is no particular restriction of the solvent provided that it has no adverse effect on the reaction and can dissolve the starting material to some extent. A preferred solvent is a halogeno hydrocarbon derivative such as methylene chloride, chloroform or carbon tetrachloride, or an alcohol derivative such as methanol or ethanol, preferably methanol.
A solution of trifluoromethanesulfonyl azide (0.4N) in methylene chloride is used as an azidation regent.
A preferred base is dimethylaminopyridine.
The reaction temperature is between xe2x88x9220 and 30xc2x0 C., preferably between 15 and 25xc2x0 C.
The reaction time is from 3 to 24 hours, preferably from 8 to 24 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step A2)
This step is a process for the preparation of compound (IV) through alkylation, alkenylation or alkynylation of the 3-hydroxy group of compound (III). This process is accomplished by treatment of an alkoxide derivative of compound (III), which is prepared by reaction of compound (III) with a strong base, with an alkylating, alkenylating or alkynylating reagent in an inert solvent.
The solvent is an ether derivative such as dioxane or tetrahydrofiran, an amide derivative such as formnamide or dimethylformamide, or an aromatic hydrocarbon such as benzene or toluene, preferably dimethylformamide.
The alkylating agent is a halogeno hydrocarbon derivative or a sulfonic acid ester, preferably a sulfonic acid ester. In this step a compound of formula R8OSO2CH3 (R8 is as defined above) may be used.
The base is an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, an alkyllithium derivative such as n-butyllithium or tert-butyllithium, or an alkali metal hydride such as sodium hydride or potassium hydride, preferably sodium hydride.
The reaction temperature is between xe2x88x9278xc2x0 C. and 80xc2x0 C., preferably between 0xc2x0 C. and 60xc2x0 C.
The reaction time varies depending on the reaction temperature, the starting material, the reagent and the solvent; it is usually from 2 to 24 hours, preferably from 2 to 8 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step A3)
This step is a process for preparation of compound (V) through removal of the 1-protecting group of compound (IV). This process is accomplished by isomerization of the 1-allyl group of compound (IV) by a metal catalyst in an inert solvent followed by hydrolysis.
The metal catalyst is a complex of palladium, rhodium or iridium, preferably (1,5-cyclooctadiene)bis(methyldiphenylphosphine)iridium(I) hexafluorophosphate ([Ir(COD)(PMePh2)2]PF6).
The solvent is a halogeno hydrocarbon derivative such as methylene chloride, chloroform or carbon tetrachloride, an ether derivative such as ether, dioxane or tetrahydrofuran, an ester derivative such as ethyl acetate, or a nitrile derivative such as acetonitrile, preferably an ether derivative, more preferably tetrahydrofuran.
The reaction temperature is between 0 and 50xc2x0 C., preferably between 5 and 25xc2x0 C.
The reaction time is from 10 minutes to 24 hours, preferably from 30 minutes to 5 hours.
The hydrolysis of an isomerized vinyl ether derivative is conducted with a mineral acid such as hydrochloric acid or sulfuric acid, an organic acid such as p-toluenesulfonic acid, or iodine in an aqueous solution, preferably iodine in a mixture of pyridine and water.
The reaction temperature is between 0 and 100xc2x0 C., preferably between 25 and 45xc2x0 C.
The reaction time is from 10 minutes to 24 hours, preferably from 30 minutes to 5 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step A4)
This step is a process for preparation of the trichloroacetimidate compound (VI). This process is accomplished by treatment of compound (V) having a 1-hydroxy group with trichloroacetonitrile in an inert solvent in the presence of a base.
The solvent is a halogeno hydrocarbon derivative such as methylene chloride, chloroform or carbon tetrachloride, an ether derivative such as ether, dioxane or tetrahydrofuran, an ester derivative such as ethyl acetate, or a nitrile derivative such as acetonitrile, preferably a halogeno hydrocarbon derivative, more preferably methylene chloride.
The base is an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or an inorganic base such as sodium hydride, potassium carbonate or cesium carbonate, preferably an organic base, more preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
The reaction temperature is between xe2x88x9225 and 50xc2x0 C., preferably between 0 and 25xc2x0 C.
The reaction time is from 10 minutes to 24 hours, preferably from 30 minutes to 2 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step A5)
This step is a process for preparation of the 1-cyano compound (VII). This process is accomplished by treatment of compound (VI) with a cyanating reagent in the presence of a catalyst in an inert solvent.
There is no particular restriction of the reaction solvent provided that it has no adverse effect on the reaction and can dissolve the starting material to some extent. The solvent is a nitrile derivative such as acetonitrile, or a halogeno hydrocarbon derivative such as methylene chloride, chloroform, carbon tetrachloride or dichloroethane, preferably a halogeno hydrocarbon derivative, more preferably methylene chloride.
The cyanating reagent is sodium cyanide, potassium cyanide, or trimethylsilyl cyanide, preferably trimethylsilyl cyanide.
The catalyst is a Lewis acid such as tin tetrachloride, trifluoroborane etherate, aluminium chloride, iron (II) chloride or trimethylsilyl triflate, preferably trimethylsilyl triflate.
The reaction temperature is between xe2x88x9240xc2x0 C. and 100xc2x0 C., preferably between 10xc2x0 C. and 40xc2x0 C.
The reaction time varies depending on the reaction temperature, the reagent and the solvent. It is usually from 10 minutes to 10 hours, preferably from 30 minutes to 5 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step A6)
This step is a process for preparation the of 2-amino compound (VIII). This process is accomplished by reduction of the azide group of compound (VII) with a reducing reagent in an inert solvent.
There is no particular restriction of the reaction solvent provided that it has no adverse effect on the reaction and can dissolve the starting material to some extent. Such a solvent is an ether derivative miscible with water, such as tetrahydrofuran or dioxane, preferably tetrahydrofuran.
The reducing reagent of azide group is a mixture of phosphine derivatives and aqeuous ammonia, for example a trialkylphosphine and aqueous ammonia solution such as trimethylphosphine or triethylphosphine and aqueous ammonia solution or a triarylphosphine and aqueous ammonia solution such as triphenylphosphine and aqueous ammonia solution, preferably triphenylphosphine and aqueous ammonia solution.
The reduction reaction time is from 1 to 24 hours, preferably 1 hour.
The reaction temperature is between 0 and 50xc2x0 C., preferably between 0xc2x0 C. and 25xc2x0 C.
The reaction temperature of the reaction of compound (VII) with a mixture of a phosphine derivative and aqueous ammonia solution is between 0 and 50xc2x0 C., preferably room temperature.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step A7)
This step is a process for preparation of compound (IX) through acylation of the 2-amino group of compound (VIII). This process is accomplished by treatment of compound (VIII) with an acylating reagent.
The acylating reagent is a carboxylic acid derivative of formula R9OH (wherein R9 is as defined above).
The solvent is an ether derivative such as dioxane or tetrahydrofuran, a halogeno hydrocarbon derivative such as methylene chloride, chloroform or carbon tetrachloride, or an amide derivative such as N,N-dimethylfoarnamide, preferably a halogeno hydrocarbon derivative, more preferably methylene chloride.
As a condensation reagent, dicyclohexylcarbodiimide may be used. Addition of 4-(dimethylamino)pyridine to the reaction mixture accelerates the reaction and depresses formation of by-products of the reaction.
The reaction temperature is between 0 and 50xc2x0 C., preferably between 15 and 25xc2x0 C. (room temperature).
The reaction time is from 1 to 24 hours, preferably 1 to 5 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedure, for example recrystallization, silica gel chromatography or the like.
(Step A8)
This step is a process for preparation of compound (X) through removal of the 4-and 6-protecting group of compound (IX), conversion of the 1-nitrile group to a carboxy group and esterification. This process is accomplished by acid hydrolysis of compound (IX) in an inert solvent followed by treatment with an esterification reagent.
The solvent for hydrolysis is a water-miscible solvent, for example an alcohol derivative such as methanol or ethanol, an ether derivative such as diethyl ether, diisopropyl ether or tetrahydrofuran, a nitrile derivative such as acetonitrile, an amide derivative such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, preferably an ether derivative (dioxane).
The acid for hydrolysis is a mineral acid such as hydrochloric acid or sulfuric acid, preferably hydrochloric acid.
The reaction temperature is between 20 and 100xc2x0 C., preferably between 50 and 80xc2x0 C.
The reaction time is from 1 to 10 hours, preferably 2 to 5 hours.
After the reaction the mixture is concentrated in vacuo to afford the crude product which can be used in the next step of the reaction without purification.
There is no paticular restriction of the esterification reagent provided that it can be hydrolyzed by acid to yield a parent acid. Such an esterification reagent is diazomethane or diphenyldiazomethane, preferably diphenyldiazomethane.
The solvent is an ether derivative such as dioxane or tetrahydrofuran, a halogeno hydrocarbon derivative such as methylene chloride, chloroform or carbon tetrachloride, or an amide derivative such as dimethylformamide, preferably an amide derivative, more preferably dimethylformamide.
The reaction temperature is between 0 and 100xc2x0 C., preferably between 25 and 60xc2x0 C.
The reaction time is from 30 minutes to 24 hours, preferably 1 to 10 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
Compound (I) can be produced by a condensation reaction of compound (X) obtained in this step with compound (XXI), (XXIX) or (XXXII) described below.
(Method Ba)
(Step Ba1)
This step is a process for preparation of compound (XII) through alkylation of the 3-hydroxy group of compound (XI). This process is accomplished by a similar procedure to that described in Step A2.
The alkylation reagent is a sulfonic acid ester of formula R10OSO2CH3 (wherein R10 is as defined above).
(Step Ba2)
This step is a process for preparation of compound (XIII) through removal of the 2-protecting group of compound (XII). This process is accomplished by treatment of compound (XII) with a base in an inert sovent.
The solvent is an alcohol derivative such as methanol or ethanol, an ether derivative such as diethyl ether or tetrahydrofuran, a nitrile derivative such as acetonitrile, or a ketone derivative such as acetone or methyl ethyl ketone, preferably an alcohol derivative (ethanol).
The base is an alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or an alkali metal alkoxide such as sodium methoxide or sodium ethoxide, preferably an alkali metal hydroxide.
The reaction temperature is between 0xc2x0 C. and 100xc2x0 C., preferably between 25xc2x0 C. and 80xc2x0 C.
The reaction time is from 30 minutes to 24 hours, preferably 1 to 5 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step Ba3)
This step is a process for preparation of compound (XIV) through protection of the 2-amino group of compound (XIII). This process is accomplished by treatment of compound (XIII) a with protecting reagent in the presence of a base in an inert solvent.
The solvent is a halogenated hydrocarbon derivative such as methylene chloride, chloroform or carbon tetrachloride, an ether derivative such as ether, dioxane or tetrahydrofuran, or a nitrile derivative such as acetonitrile, preferably a halogenated hydrocarbon derivative, more preferably methylene chloride.
The protecting reagent which does not prevent the glycosidation of CI step 1 is preferably trichloroethoxycarbonyl chloride.
The base is a pyridine derivative such as pyridine or dimethylaminopyridine, a trialkylamine derivative such as triethylamine or tributylamine, or an alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate, preferably an alkali metal bicarbonate (sodium bicarbonate).
The reaction temperature is between xe2x88x9220xc2x0 C. and 60xc2x0 C., preferably between 0xc2x0 C. and 25xc2x0 C.
The reaction time is from 30 minutes to 24 hours, preferably 1 to 5 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step Ba4)
This step is a process for removal of the 4- and 6-protecting group of compound (XIV). This process is accomplished by treatment of compound (XIV) with an acid.
The acid is an inorganic acid such as hydrochloric acid or sulfuric acid or an organic acid such as acetic acid or oxalic acid, preferably an organic acid, more preferably acetic acid diluted with water (70-90%).
The reaction temperature is between 20 and 100xc2x0 C., preferably between 40 and 80xc2x0 C.
The reaction time is from 10 minutes to 24 hours, preferably 30 minutes to 5 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step Ba5)
This step is a process for preparation of compound (XVI) through selective protection of the 6-hydroxy group of compound (XV). This process is accomplished by treatment of compound (XV) with an esterification reagent in the presence of a base in an inert solvent.
The protecting reagent which can selectively be removed to afford the 6-hydroxy compound in good yield is, for example, an alkyloxycarbonyl halide such as tert-butoxycarbonyl chloride, an aralkyloxycarbonyl halide such as benzyloxycarbonyl chloride, a halogeno-alkoxycarbonyl halide such as trichloroethoxycarbonyl chloride, or an alkyl halide substituted with aryl groups such as triphenylmethyl chloride or diphenylmethyl chloride, preferably benzyloxycarbonyl chloride.
The base is an organic base such as pyridine, dimethylaminopyridine, triethylamine or N,N-dimethylaniline, preferably pyridine.
The solvent is a halogenated hydrocarbon derivative such as methylene chloride, chloroform or carbon tetrachloride, an ether derivative such as ether, dioxane or tetrahydrofuran, or an ester derivative such as ethyl acetate, preferably a halogenated hydrocarbon derivative, more preferably methylene chloride.
The reaction temperature is between xe2x88x9250 and 50xc2x0 C., preferably between xe2x88x9210 and 30xc2x0 C.
The reaction time is from 10 minutes to 24 hours, preferably 30 minutes to 5 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step Ba6)
This step is a process for preparation of compound (XVII) through phosphorylation of the 4-hydroxy group of compound (XVI). This process is accomplished by treatment of compound (XVI) with a phosphorylating reagent in the presence of a base in an inert solvent.
The phosphorylating reagent is a phosphoric acid halide of formula (R11xe2x80x94O)2P(xe2x95x90O)X, wherein X is a halogen atom such as a chlorine, bromine or iodine atom, preferably a chlorine atom, the group R11 of which can be removed to afford compound (I) in good yield when phosphoric acid ester compound (XXXV) is converted to compound (I) by deprotection of a protecting group of compound (XXXV). A preferred phosphorylating reagent is benzylphosphoryl chloride or phenylphosphoryl chloride.
The base is an organic base such as pyridine, dimethylaminopyridine, triethylamine or N,N-dimethylaniline, preferably dimethylaminopyridine.
The solvent is a halogenated hydrocarbon derivative such as methylene chloride, chloroform or carbon tetrachloride, an ether derivative such as ether, dioxane or tetrahydrofuran, or an ester derivative such as ethyl acetate, preferably a halogenated hydrocarbon derivative (methylene chloride).
The reaction temperature is between 0 and 50xc2x0 C., preferably between 5 and 30xc2x0 C.
The reaction time is from 10 minutes to 24 hours, preferably 30 minutes to 5 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step Ba7)
This step is a process for preparation of compound (XVIII) through removal of the p-methoxybenzyl group of compound (XVII) when compound (XVII) has a p-methoxybenzyl group in the 3-alkyl group (R10). This process is accomplished by treatment of compound (XVII) with a deprotecting reagent in the presence of water in an inert solvent.
This process is optional and if not necessary, Ba9 step can be performed.
The solvent is a nitrile derivative such as acetonitrile or a halogenated hydrocarbon derivative such as methylene chloride or chloroform, preferably methylene chloride.
The deprotecting reagent is ceric ammonium nitrate (CAN), N-bromosuccinimide (NBS), triphenylcarbenium tetrafluoroborate, or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), preferably 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).
The reaction temperature is between 0 and 30xc2x0 C., preferably between 15 and 25xc2x0 C.
The reaction time is from 30 minutes to 8 hours, preferably 1 to 5 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step Ba8)
This step is a process for preparation of compound (XIX) through acylation of a hydroxy group in the 3-alkyl group (R12) of compound (XVIII). This process is accomplished by treatment of compound (XVIII) with an acylating reagent in the presence of a base in an inert solvent. This step is also optional.
The acylating reagent is preferably a C12-C14 alkanoyl chloride, more preferably myristoyl chloride.
The solvent is an ether derivative such as tetrahydrofuran or dioxane, a halogenated hydrocarbon derivative such as methylene chloride, chloroform or carbon tetrachloride, or an amide derivative such as N,N-dimethylamide, preferably an ether derivative, more preferably tetrahydrofuran.
The base is an organic base such as pyridine, dimethylaminopyridine, triethylamine or N,N-dimethylaniline, preferably dimethylaminopyridine or triethylamine.
The reaction temperature is between 0 and 80xc2x0 C., preferably between 0 and 25xc2x0 C.
The reaction time is from 1 to 24 hours, preferably 1 to 8 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step Ba9)
This step is a process for preparation of compound (XX) through removal of the 1-allyl group of compound (XIX). This process is accomplished by a similar procedure to that described in Step A3.
(Step Ba10)
This step is a process for preparation of the trichloroacetimidate derivative (XXI) which is one of the important intermediates. This process is accomplished by treatment with trichloroacetonitrile in the presence of a base in an inert solvent in a similar manner to that described in Step A4.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step Bb1)
This step is a process for preparation of compound (XXII) through selective protection of the 6-hydroxy group of compound (XV) which is obtained in Step Ba4. This process is accomplished by treatment of compound (XV) with a silylating reagent in the presence of a base in an inert solvent.
The silylating reagent is a trialkylsilyl halide or trialkylsilyl trifluoromethanesulfonate of formula (R14)3SiXxe2x80x2 (wherein R14 is as defined above, and Xxe2x80x2 is a halogen atom or a trifluoromethanesulfonyl group), preferably tert-butyldimethylsilyl chloride.
The base is a pyridine derivative such as pyridine or dimethylaminopyridine, a trialkylamine such as triethylamine or tributylamine, an aniline derivative such as aniline or N,N-dimethylaniline, or a lutidine derivative such as 2,6-lutidine, preferably dimethylaminopyridine.
The solvent is a halogenated hydrocarbon derivative such as methylene chloride, chloroform or carbon tetrachloride, an ether derivative such as ether, tetrahydrofuran or dioxane, or a nitrile derivative such as acetonitrile, preferably methylene chloride.
The reaction temperature is between 0 and 50xc2x0 C., preferably between 15 and 25xc2x0 C.
The reaction time is from 1 to 24 hours, preferably 1 to 8 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step Bb2)
This step is a process for preparation of compound (XXIII) through phosphorylation of the 4-hydroxy group of compound (XXII). This process is accomplished by a similar procedure to that described in Step Ba6.
(Step Bb3)
This step is a process for preparation of compound (XXIV) through removal of a protecting group in the 3-alkyl group (R10) of compound (XXIII). This process is accomplished by a similar procedure to that described in Step Ba7.
This process is optional and if not necessary, Step Bb5 can be performed.
(Step Bb4)
This step is a process for preparation of compound (XXV) through acylation of a hydroxy group in the 3-alkyl group (R12) of compound (XXIV). This process is accomplished by a similar procedure to that described in Step Ba8. This step is also optional.
(Step Bb5)
This step is a process for preparation of compound (XXVI) through removal of the 6-protecting group of compound (XXV). This process is accomplished by hydrolysis of compound (XXV) with acid in an inert solvent.
The acid is an inorganic acid such as hydrochloric acid or sulfuric acid or an organic acid such as acetic acid or oxalic acid, preferably 3N hydrochloric acid.
The solvent is a water-miscible solvent such as dioxane or tetrahydrofuran, preferably tetrahydrofuran.
The reaction temperature is between 20 and 80xc2x0 C., preferably between 20 and 50xc2x0 C.
The reaction time is from 30 minutes to 24 hours, preferably 1 to 8 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step Bb6)
This step is a process for preparation of compound (XXVII) through alkylation of the 6-hydroxy group of compound (XXVI). When R15 is a C1-C6 alkyl group this process is accomplished by method (1) and when R15 is a methyl group, this process may also be accomplished by method (2).
Method (1): In the case when R15 is a C1-C6 alkyl group:
Method (1) is accomplished by treatment of compound (XXVI) with an alkylating reagent in the presence of a base or silver (II) oxide (AgO) in an inert solvent.
There is no particular restriction of the solvent provided that it has no adverse effect on the reaction and can dissolve the starting material to some extent. Such a solvent is an aliphatic hydrocarbon drivative such as hexane, heptane or ligroin, an aromatic hydrocarbon derivative such as benzene, toluene or xylene, a halogeno hydrocarbon derivative such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane or chlorobenzene, an ester derivative such as ethyl acetate, propyl acetate or diethyl carbonate, an ether derivative such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, a nitrile derivative such as acetonitrile or isobutyronitrile, or an amide derivative such as formamide, N,N-dimethylformamide or N,N-dimethylacetamide, preferably an ether derivative.
The base is an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate, an alkali metal hydride such as sodium hydride or potassium hydride, or an organic base such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(tert-butyl)-4-methylpyridine, N,N-dimethylaniline, N,N-diethylaniline, 5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably an organic base, more preferably triethylamine, DBN or DBU.
The alkylating reagent is a compound of formula R15Z (wherein R15 is as defined above, and Z is an iodine atom, a bromine atom, a chlorine atom, a p-toluenesulfonyloxy group, or a methanesulfonyloxy group).
The reaction temperature is between 0xc2x0 C. and 100xc2x0 C., preferably between 0xc2x0 C. and 30xc2x0 C.
The reaction time is from 10 minutes to 24 hours, preferably 1 to 18 hours. Method (2): In the case when R15 is a methyl group:
Method (2) is accomplished by treatment of compound (XXVI) with trimethyloxonium tetrafluoroborate in the presence of a base in an inert solvent.
The solvent is an ether derivative such as ether, tetrahydrofuran or dioxane, a halogeno hydrocarbon derivative such as methylene chloride, chloroform or carbon tetrachloride, or an amide derivative such as formamide, N,N-dimethylformamide or N,N-dimethylacetamide, preferably methylene chloride.
The base is preferably 2,6-di(tert-butyl)-4-methylpyridine.
The reaction temperature is between xe2x88x9250xc2x0 C. and 100xc2x0 C., preferably between 0xc2x0 C. and 30xc2x0 C.
The reaction time is from 1 to 24 hours, preferably 2 to 5 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step Bb7)
This step is a process for preparation of compound (XXVIII) through removal of the 1-allyl group of compound (XXVII). This process is accomplished by a similar procedure to that described in Step A3.
(Step Bb8)
This step is a process for preparation of the trichloroacetimidate derivative (XXIX) which is one of the important intermediates. This process is accomplished by a similar procedure to that described in Step Ba10 using compound (XXVIII).
(Step Bc1)
This step is a process for preparation of compound (XXX) through conversion of the 6-hydroxy group of compound (XXVI) obtained in Step Bb5 to a halogen or hydrogen atom.
(Step 1 Bc1)
This step is a process for preparation of compound (XXX) wherein R16 is a halogen atom. This process is acomplished by one of methods (1), (2) and (3) described below.
Method (1) In the case when R16 is a fluorine atom:
This process is accomplished by treatment of compound (XXVI) with a fluorination reagent in an inert solvent.
The solvent is a halogeno hydrocarbon derivative such as methylene chloride or fluorotrichloromethane, or an ether derivative such as ether or 1,2-dimethoxyethane, preferably methylene chloride.
The fluorination reagent is, for example, (2-fluoroethyl)dimethylamine or (diethylamino)sulfur trifluoride (DAST), preferably DAST.
The reaction temperature is between xe2x88x9278xc2x0 C. and 25xc2x0 C., preferably between 0xc2x0 C. and 25xc2x0 C.
The reaction time is from 1 to 18 hours, preferably 1 to 5 hours.
Method (2) In the case when R16 is a chlorine or bromine atom:
This process is accomplished by treatment of compound (XXVI) with phosphorus trichloride, phosphorus tribromide, phosphoryl chloride, phosphoryl bromide, thionyl chloride or thionyl bromide in an inert solvent.
The solvent is preferably a halogeno hydrocarbon derivative such as methylene chloride, chloroform or carbon tetrachloride.
The reaction temperature is between xe2x88x9250xc2x0 C. and 50xc2x0 C., preferably between xe2x88x9210xc2x0 C. and 30xc2x0 C.
The reaction time is from 1 to 18 hours, preferably 1 to 5 hours.
Method (3) In the case when R16 is an iodine atom:
This process is accomplished by treatment of compound (XXVI) with iodine and triphenylphosphine in an inert solvent.
There is no particular restriction of the solvent provided that it has no adverse effect on the reaction and it can dissolve the starting material to some extent. Such a solvent is an aliphatic hydrocarbon drivative such as hexane, heptane or ligroin, an aromatic hydrocarbon derivative such as benzene, toluene or xylene, a halogeno hydrocarbon derivative such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane or chlorobenzene, an ester derivative such as ethyl acetate, propyl acetate or diethyl carbonate, an ether derivative such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, an alcohol derivative such as methanol or ethanol, or an amide derivative such as formamide, N,N-dimethylformamide or N,N-dimethylacetamide, preferably an ether derivative.
The reaction temperature is between xe2x88x9250xc2x0 C. and 100xc2x0 C., preferably between 0xc2x0 C. and 30xc2x0 C.
The reaction time is from 1 to 18 hours, preferably 1 to 5 hours.
After the reaction the desired compound (XXX) is isolated by conventional procedures. For example, the reaction mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Bc1 Step 2)
This step is a process for preparation of compound (XXX) wherein R16 is a hydrogen atom. This process is accomplished by treatment of a compound, which is obtained in Bc1 Step 1 Method (2) and wherein R16 is a bromine atom, with tributyltin hydride or lithium aluminium hydride in an inert solvent.
The solvent is an aliphatic hydrocarbon drivative such as hexane, heptane or ligroin, an aromatic hydrocarbon derivative such as benzene, toluene or xylene, or an ether derivative such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, preferably an ether derivative.
The reaction temperature is between xe2x88x9250xc2x0 C. and 50xc2x0 C., preferably between xe2x88x9210xc2x0 C. and 30xc2x0 C.
The reaction time is from 10 minutes to 16 hours, preferably 1 to 8 hours.
After the reaction the desired compound (XXX) is isolated by conventional procedures. For example, the reaction mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step Bc2)
This step is a process for preparation of compound (XXXI) through removal of the 1-allyl group of compound (XXX). This process is accomplished by a similar procedure to that described in Step A3.
(Step Bc3)
This step is a process for preparation of the trichloroacetimidate derivative (XXXII) which is one of the important intermediates. This process is accomplished by a similar procedure to that described in Step Ba10.
(Step C1)
This step is a process for preparation of compound (XXXIII) having lipid A structure through a reaction of an intermediate (XXI), (XXIX) or (XXXII) with an intermediate (X). This process is accomplished by glycosidation of a compound (XXI), (XXIX) or (XXXII) with a compound (X) in the presence of an acid catalyst in an inert solvent.
The acid catalyst is a Lewis acid such as tin tetrachloride, trifluoroborane etherate, aluminium chloride, iron (II) chloride or trimethylsilyl triflate, preferably trimethylsilyl triflate.
The solvent is a halogeno hydrocarbon such as methylene chloride or chloroform, an ether derivative such as diethyl ether, a nitrile derivative such as acetonitrile, an aromatic hydrocarbon derivative such as benzene or toluene, or an amide derivative such as N,N-dimethylformamide, preferably a halogeno hydrocarbon derivative, more preferably methylene chloride.
The reaction temperature is between xe2x88x92100 and 25xc2x0 C., preferably between xe2x88x9278 and 0xc2x0 C.
The reaction time is from 10 minutes to 10 hours, preferably 30 minutes to 5 hours.
After the reaction the mixture is neutralized, concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
(Step C2)
This step is a process for preparation of compound (XXXIV) through removal of the trichloroethoxycarbonyl group of compound (XXXIII) followed by conversion to acyl group R3. This process is accomplished by treatment of compound (XXXIII) with a deprotecting reagent in an inert solvent and treatment of the deprotected product with acylating reagent.
The solvent of deprotection reaction is acetic acid.
The deprotecting reagent for the trichloroethoxycarbonyl group is zinc powder.
The reaction temperature is between 0 and 80xc2x0 C., preferably between 10 and 30xc2x0 C.
The reaction time is from 1 to 24 hours, preferably 1 to 8 hours.
The acylating reagent is a carboxylic acid of formula R3OH or an acid anhydride of formula (R3)2O (wherein R3 is as defined above). The acylation can be conducted in a similar procedure to that described in Step A7.
(Step C3)
This step is a process for preparation of compound (I) of the present invention through removal of the 1-protecting group, protecting groups for hydroxy groups R8, R9, R13 and R7 and protecting group R11 for the phosphoric acid group. This process is accomplished by procedures described by Greene, T. W. et al., xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons (1991) or procedures described below. In addition, when compound (XXXIV) has several kinds of protecting groups, removal of these protecting groups can be achieved step by step in an appropriate combination of deprotection reactions depending on the protecting groups.
Deprotection (1) in the case that protecting group is an aralkyl group:
This step is a process of removal of aralkyl group. This process is accomplished by catalytic reduction in an atmosphere of hydrogen in the presence of a catalyst in an inert solvent.
The catalyst is palladium on carbon, palladium hydroxide, palladium hydroxide on carbon or palladium black, preferably palladium on carbon.
The solvent is an ether derivative such as tetrahydrofuran, dioxane or ether, an ester derivative such as ethyl acetate, an alcohol derivative such as methanol or ethanol, or an organic acid derivative such as acetic acid or formic acid, preferably ethanol.
The reaction temperature is between 0 and 50xc2x0 C., preferably between 15 and 25xc2x0 C.
The reaction time is from 1 to 48 hours, preferably 1 to 24 hours.
After the reaction the catalyst is removed by filtration. The filtrate is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, silica gel chromatography or the like.
Deprotection (2) in the case that protecting group is a diphenylmethyl group:
This step is a process for removal of diphenylmethyl group This process is accomplished by catalytic reduction in an atmosphere of hydrogen by similar procedure to that described in Deprotection (1) or by treatment with an acid in an inert solvent. When compound (XXXIV) has a double bond or triple bond the treatment of compound (XXXIV) with an acid can be used.
There is no particular restriction of the acid provided that it is an usual Bronsted or Lewis acid. A preferred acid is an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid, or an organic acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid.
There is no particular restriction of the solvent provided that it has no adverse effect on the reaction and it can dissolve the starting material to some extent. Such a solvent is an aliphatic hydrocarbon drivative such as hexane, heptane or ligroin, an aromatic hydrocarbon derivative such as benzene, toluene or xylene, a halogeno hydrocarbon derivative such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane or chlorobenzene, an ester derivative such as ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate, an ether derivative such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, an alcohol derivative such as methanol, ethanol, propanol, butanol or isoamyl alcohol, a ketone derivative such as acetone, methyl ethyl ketone or cyclohexanone, water or mixtures of these solvents, preferably a halogeno hydrocarbon derivative, an ester derivative or an ether derivative.
The reaction temperature and reaction time vary depending on the nature of the starting material, solvent and acid, and the concentration of acid. The reaction temperature is usually between xe2x88x9210 and 100xc2x0 C., preferably between xe2x88x925 and 50xc2x0 C. The reaction time is usually from 5 minutes to 48 hours, preferably 30 minutes to 10 hours.
After the reaction the desired product is isolated by conventional procedures. For example the reaction mixture is concentrated and then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, reprecipitation, silica gel chromatography or the like.
Deprotection (3) in the case that R11 in a protecting group of phosphoric acid group is a phenyl group:
This process is accomplished by catalytic reduction in the presence of a catalyst in an inert solvent.
The catalyst is preferably platinum oxide.
The solvent is an ether derivative such as tetrahydrofuran, dioxane or ether, an ester derivative such as ethyl acetate, an alcohol derivative such as methanol or ethanol, or an organic acid derivative such as acetic acid or formic acid, preferably tetrahydrofuran.
The reaction temperature is between 0 and 50xc2x0 C., preferably between 15 and 25xc2x0 C.
The reaction time is from 1 to 48 hours, preferably 1 to 24 hours.
After the reaction the catalyst is removed by filtration. The filtrate is concentrated in vacuo to afford the desired product which, if necessary, is further purified by conventional procedures, for example recrystallization, reprecipitation, silica gel chromatography or the like.
An ester derivative of compound (I) of the present invention may be prepared by treatment with an esterification reagent in a conventional procedure. The esterification reaction is conducted, if necessary, before or after protection of a hydroxy group or before or after deprotection of a hydroxy group.
Esterification method (1) where an alkyl halide derivative is used in order to prepare a desired ester derivative.
Esterification method (2) where an alcohol derivative is used in order to prepare a desired ester derivative.
In esterification method (1):
There is no particular restriction of the solvent provided that it has no adverse effect on the reaction and can dissolve the starting material to some extent. A preferred solvent is an aliphatic hydrocarbon drivative such as hexane or heptane, an aromatic hydrocarbon derivative such as benzene, toluene or xylene, a halogeno hydrocarbon derivative such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane or dichlorobenzene, an ether derivative such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether, a ketone derivative such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone, a nitrile derivative such as acetonitrile or isobutyronitrile, or an amide derivative such as formamide, N,N-dimethylformamide, or N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, or hexamethylphosphoric triamide.
In the esterification method (1) a base is used as a catalyst. There is no particular restriction of the base provided that it can be used as a base in a conventional reaction. A preferred base is an inorganic base, for example an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate, an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate, an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide, an alkali metal fluoride such as sodium fluoride or potassium fluoride; an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide or lithium methoxide; an alkali metal mercaptan such as sodium methylmercaptan, or sodium ethylmercaptan; an organic base such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); or an organometallic base such as butyllithium, lithium diisopropylamide or lithium bis(trimethylsilyl)anide.
The reaction temperature is usually between xe2x88x9220xc2x0 C. and 120xc2x0 C., preferably between 0xc2x0 C. and 80xc2x0 C.
The reaction time is from 0.5 to 10 hours.
In esterification method (2):
This process is accomplished by treatment with a condensation reagent in the presence or absence of a base in an ineret solvent.
The condensation reagent is described below:
(a) a combination of a phosphoric ester derivative such as diethylphosphoryl cyanide or diphenylphosphoryl azide and a base described below,
(b) a carbodiumide derivative such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,
a combination of a carbodiimide derivative described above and a base described below,
a combination of a carbodiimide derivative described above and an N-hydroxy derivative such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbomen-2,3-dicarboxyimide,
(c) a combination of a disulfide derivative such as 2,2xe2x80x2-dipyridyl disulfide, or 2,2xe2x80x2-dibenzothiazolyl disulfide and a phosphine derivative such as triphenylphosphine or tributylphosphine,
(d) a carbonate derivative such as N,Nxe2x80x2-disuccinimidyl carbonate, di-2-pyridyl carbonate or S,Sxe2x80x2-bis(1-phenyl-1H-tetrazol-5-yl)dithiocarbonate,
(e) a phosphinic chloride derivative such as N,Nxe2x80x2-bis(2-oxo-3-oxazolidinyl)phosphinic chloride,
(f) an oxalate derivative such as N,Nxe2x80x2-disuccinimidyl oxalate, N,Nxe2x80x2-diphthalimide oxalate, N,Nxe2x80x2-bis(5-norbornen-2,3-dicarboimidyl) oxalate, 1,1xe2x80x2-bis(benzotriazolyl) oxalate, 1,1xe2x80x2-bis(6-chlorobenzotriazolyl) oxalate, or 1,1xe2x80x2-bis(6-trifluoromethylbenzotnazolyl) oxalate,
(g) a combination of a phosphine derivative described above and an ester or amide derivative of azodicarboxylic acid such as diethyl azodicarboxylate, or 1,1xe2x80x2-(azodicarbonyl)dipiperidine,
a combimanation of a phosphine derivative described above and a base described below,
(h) an N-lower alkyl-5-arylisooxazolium-3xe2x80x2-sulfonate derivative such as N-ethyl-5-phenylisooxazolium-3xe2x80x2-sulfonate,
(i) a diheteroaryl diselenide such as di-2-pyridyl diselenide,
(j) an arylsulfonyl triazolide derivative such as p-nitrobenzenesulfonyltriazolide,
(k) a 2-halo-1-lower alkylpyridinium halide such as 2-chloro-1-methylpyridinium iodide,
(l) an imidazole derivative such as 1,1xe2x80x2-oxalyldiimidazole or N,Nxe2x80x2-carbonyldiimidazole,
(m) a 3-lower alkyl-2-halo-benzothiazolium fluoroborate derivative such as 3-ethyl-2-chloro-benzothiazolium fluoroborate,
(o) a phosphate derivative such as phenyl dichlorophosphate, or polyphosphate ester,
(p) a halogenosulfonyl isocyanate derivative such as chlorosulfonyl isocyanate,
(q) a halogenosilane derivative such as trimethylsilyl chloride or triethylsilyl chloride,
(r) a combination of a lower alkanesulfonyl halide derivative such as methanesulfonyl chloride and a base described below,
(s) an N,N,Nxe2x80x2,Nxe2x80x2-tetra lower alkyl halogeno formamidium chloride derivative such as N,N,Nxe2x80x2,Nxe2x80x2-tetramethyl chloroformamidium chloride.
A preferred condensation reagent is a carbodiimide derivative, a combination of a phosphine derivative and an ester derivative of azodicarboxylic acid or a combination of a phosphine derivative and an amide derivative of azodicarboxylic acid.
In esterification method (2) there is no particular restriction of the solvent provided that it has no adverse effect on the reaction and can dissolve the starting material to some extent. A preferred solvent is an aliphatic hydrocarbon drivative such as hexane or heptane, an aromatic hydrocarbon derivative such as benzene, toluene or xylene, a halogeno hydrocarbon derivative such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene, an ester derivative such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate, an ether derivative such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or di(ethylene glycol) dimethyl ether, a nitrile derivative such as acetonitrile or isobutyronitrile, or an amide derivative such as fornamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide.
In the esterification method (2) a base may be used as a catalyst. There is no particular restriction of the base provided that it can be used as a base in a conventional reaction. A preferred base is an organic base such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline or N,N-diethylaniline.
In addition, in esterification method (2):
a combination of a catalytic amount of 4-(N,N-dimethylamino)pyridine or 4-pyrrolidinopyridine and another base can also be used,
a dehydrating agent such as molecular sieves can be used in order to conduct the esterification effectively,
a quaternary ammonium salt such as benzyltriethylammonium chloride or tetrabutylammonium chloride, a crown ether derivative such as dibenzo-18-crown-6,
or an acid capturing agent such as 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-one can be added to the reaction mixture.
The reaction temperature is between xe2x88x9220xc2x0 C. and 80xc2x0 C., preferably between 0xc2x0 C. and room temperature.
The reaction time varies dependent on the reaction temperature, the starting material, the reagent and the solvent. It is usually from 10 minutes to 3 days, preferably 30 minutes to 1 day.
Particularly in the case that the ester-forming group is a lower alkyl group, the esterification reaction is accomplished by treatment with an alcohol such as methanol, ethanol, propanol, or butanol in the presence of an acid catalyst in a solvent.
There is no particular restriction of the solvent provided that it has no adverse effect on the reaction and can dissolve the starting material to some extent. A preferred solvent is an alcohol derivative which is the same as esterifying reagent alcohol, an aliphatic hydrocarbon derivative such as hexane or heptane, an aromatic hydrocarbon derivative such as benzene, toluene or xylene, a halogeno hydrocarbon derivative such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene, an ether derivative such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or di(ethylene glycol) dimethyl ether, a ketone derivative such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone, a nitrile derivative such as acetonitrile or isobutyronitrile, or an amide derivative such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide; a more preferred solvent is an alcohol derivative which is the same as esterifying reagent alcohol.
There is no particular restriction of the acid catalyst provided that it can be used as an acid catalyst in a conventional reaction. A preferred acid is a Bronsted acid, for example an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid, or an organic acid such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or a Lewis acid such as boron trichloride, boron trifluoride or boron tribromide, or an acidic ion exchange resin.
The reaction temperature is between 0xc2x0 C. and 100xc2x0 C., preferably between 20xc2x0 C. and 60xc2x0 C.
The reaction time is from 1 to 24 hours.
After the reaction the desired product (I) is isolated by conventional procedures. For example the reaction mixture is appropriately neutralized, if necessary insoluble material is removed by filtration and is then partitioned between an organic solvent such as ethyl acetate and water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate or the like and then is concentrated in vacuo to afford the desired product which, if desired, is further purified by conventional procedures, for example recrystallization, reprecipitation, or a conventional purification procedure.
A conventional purification procedure includes absorption column chromatography using a carrier such as silica gel, alumina, magnesium-silica gel system fluorisil, partition column chromatography using a carrier, for example a synthetic absorbent such as sephadex LH-20 (Pharmacia Co., Ltd), amberlite XAD-11 (Rohm and Haas Co., Ltd) or diaion HP-20 (Mitsubishi Chemicals Co., Ltd) or normal-phase or reverse-phase column chromatography using silica gel or alkylated silica gel (preferably high performance liquid chromatography) or a combination of these chromatographies using an appropriate eluant.
The compound (I) of the invention can be administered by a variety of routes including orally as a unit dosage such as tablets, capsules, granules, powders or syrups, or parenteral administration as a unit dosage such as injections or suppositories. These pharmaceutical formulations are prepared by well known methods using carriers which include additives such as excipients, binders, disintegrants, lubricants, stabilizers, corrigents and diluents.
The determination of a therapeutically effective amount and a prophylactically effective amount can be readily made by the physician or veterinarian (the xe2x80x9cattending clinicianxe2x80x9d), as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. The dosages may be varied depending upon the requirements of the patient in the judgment of the attending clinician, the severity of the condition being treated and the particular compound being employed. In determining the therapeutically effective amount or dose, and the prophylactically effective amount or dose, a number of factors are considered by the attending clinician, including, but not limited to: the specific condition involved; pharmacodynamic characteristics of the particular agent and its mode and route of administration; the desired time course of treatment; the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the kind of concurrent treatment (i.e., the interaction of the present invention compounds with other co-administered therapeutics); and other relevant circumstances.
Treatment can be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. A therapeutically effective prophylactical amount of a is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 50 mg/kg/day.
Compounds which are determined to be effective for the prevention or treatment of animals, e.g., dogs, rodents, may also be useful in treatment in humans. Those skilled in the art will know, based upon the data obtained in animal studies, the initial dosage and route of administration of the compound to humans. In general, the determination of dosage and route of administration in humans is expected to be similar to that used to determine administration in animals.
The identification of those patients who are in need of prophylactic treatment is well within the ability and knowledge of one skilled in the art, for example, a clinician skilled in the art, by the use of, for example, clinical tests, physical examination and medical/family history.
The present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the inventive compounds formulated together with one or more pharmaceutically acceptable carriers including additives and/or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.
The phrase xe2x80x9ctherapeutically-effective amountxe2x80x9d as used herein means that amount of compound or composition comprising the compound which is effective for producing some desired macrophage inhibiting effect at a reasonable benefit/risk ratio applicable to any medical treatment.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase xe2x80x9cpharmaceutically-acceptable carrierxe2x80x9d as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer""s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediarnine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
Formulations useful in the methods of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably 0.5 percent to 90 percent, more preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.
Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of the compound. A compound may also be administered as a bolus, electuary or paste.
In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered peptide or peptidomimetic moistened with an inert liquid diluent.
Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofiryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
Suspensions may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more inventive compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
The ointments, pastes, creams and gels may contain excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
The compound can be alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A nonaqueous suspension could be used. Sonic nebulizers are preferred because they minimize exposing the agent to shear, which can result in degradation of the compound.
Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers including stabilizers. These vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the peptidomimetic across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the peptidomimetic in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the inventive compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
The preparations of agents may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred.
The phrases xe2x80x9cparenteral administrationxe2x80x9d and xe2x80x9cadministered parenterallyxe2x80x9d as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
The phrases xe2x80x9csystemic administration,xe2x80x9d xe2x80x9cadministered systemically,xe2x80x9d xe2x80x9cperipheral administrationxe2x80x9d and xe2x80x9cadministered peripherallyxe2x80x9d as used herein mean the administration other than directly into the central nervous system, such that it enters the patient""s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
These inventive compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
These pharmaceutical preparations are prepared by standard techniques that are well known to those skilled in the art using additives. The additives are excipients (for example, organic excipients such as sugar derivatives, e.g. lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, alpha.-starch, dextrin and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low substituted hydroxyproyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose and internally bridged sodium carboxymethyl cellulose; gum Arabic; dextran; and Pullulan; and inorganic excipients such as silicate derivatives, e.g. light silicic acid anhydride, synthetic aluminum silicate and magnesium meta-silicic acid aluminate; phosphates, e.g. calcium phosphate; carbonates, e.g. calcium carbonate; and sulfates, e.g. calcium sulfate); lubricants (for example, stearic acid; metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; sodium salts of aliphatic acid; laurylsulfates such as sodium laurylsulfate and magnesium laurylsulfate; silicic acids such as silicic acid anhydride and silicic acid hydrate; and the above-mentioned starch derivatives); binders (for example, polyvinyl pyrrolidone, Macrogol and the same compounds as described in the above excipients); disintegrants (for example, the same compounds as described in the above excipients; and chemically modified starches and celluloses such as sodium Crosscarmelose, sodium carboxymethyl starch and bridged polyvinyl pyrrolidone); stabilizers (for example, para-oxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid); corrigents (for example, sweetening agents, acidifiers and aroma chemicals conventionally used); and diluents.
The dosage of compound (I) of the invention depends on the age and condition of the patient (e.g., human). A suitable dosage level for macrophage activity is 0.01 to 50 mg/kg body weight/day. The dosage may be divided into subunits administered at several times throughout the day. A suitable dosage level for inhibition of macrophage activity is 0.01 to 10 mg/kg body weight/day. The dosage may be divided into subunits administered at several times throughout the day.